Simulating Ancestrally Unbiased Tumor Evolution To Interrogate Drug Resistance

PROJECT SUMMARY
Among cancer patients of distinct ancestries, there are molecular differences in the composition of their tumors,
and their responses to therapies. These molecular distinctions extend well beyond germline differences, and
encompass somatic and non-mutational alterations as well. Compared to European-American patients, African-
American prostate cancer patients ’have a markedly higher risk of both developing and dying from prostate
cancer. This mortality is related to inevitable drug resistance, and often from bone metastases. Although access-
to-care contributes, there is also a higher risk of cancer progression for African-American patients enrolled in
active surveillance programs. Collectively, there is evidence that molecular distinctions enriched among different
ancestries can play a role in altering tumorigenesis and response to therapies.
There are significant challenges in addressing the above. Large molecular profiling cohorts of patient tumors
are underrepresented for non-European American patients, and there are only limited cell-lines derived from
such patients. We also need effective ways to rapidly model tumor evolution in vivo in an immunocompetent
and hormone-sensitive manner, to develop corresponding therapies that are biologically relevant.
To address these significant challenges, my central vision is to interrogate tumor evolution in an ancestrally
unbiased manner. This would enable us to identify powerful driver molecular alterations that are currently
underappreciated due to the limited nature of existing non-European American patient cohorts, and also develop
effective therapies against such tumors. Inspired by a subset of my own patients, the centerpiece of this proposal
is the development of BRUTE (BaRcoded Unsupervised Tumor Evolution FIGURE), an immunocompetent
organoid-based tumor graft system. The first proof-of-principle iteration of BRUTE tumors in an androgen-
dependent prostate-tissue derived system strongly identified ERF and other underappreciated oncogenic
alterations enriched uniquely among African-American patients.
Using our tractable BRUTE system and orthologous approaches, we will investigate in an ancestrally unbiased
manner A) how the anatomic niche and immune system alter the selection of tumorigenic and drug-resistant
cells, B) the biology of the future drug-resistant cells among the precancerous bulk population, and C) how to
target the molecular alterations that are enriched among non-European American patients.
This is the first tumor evolution system of which we are aware that spontaneously recapitulates molecular driver
alterations observed in underrepresented patient cohorts. Thus, we can use it to ask: why are African-American
prostate cancer patients more likely to die of bone metastases than European-American patients? Can we
detect and eliminate the future drug resistant cells in underrepresented patients’ tumors prior to drug exposure?
And can we develop targeted therapies to exploit the molecular alterations observed in African-American
prostate cancer patients?

Grant Number: 1DP2CA290244-01
NIH Institute/Center: NIH
Principal Investigator: Rohit Bose